Crystal Structure of a β-Catenin/BCL9/Tcf4 Complex

Abstract

The canonical Wnt pathway plays critical roles in embryonic development, stem cell growth, and tumorigenesis. Stimulation of the Wnt pathway leads to the association of beta-catenin with Tcf and BCL9 in the nucleus, resulting in the transactivation of Wnt target genes. We have determined the crystal structure of a beta-catenin/BCL9/Tcf-4 triple complex at 2.6 A resolution. Our studies reveal that the beta-catenin binding site of BCL9 is distinct from that of most other beta-catenin partners and forms a good target for developing drugs that block canonical Wnt/beta-catenin signaling. The BCL9 beta-catenin binding domain (CBD) forms an alpha helix that binds to the first armadillo repeat of beta-catenin, which can be mutated to prevent beta-catenin binding to BCL9 without affecting cadherin or alpha-catenin binding. We also demonstrate that beta-catenin Y142 phosphorylation, which has been proposed to regulate BCL9-2 binding, does not directly affect the interaction of beta-catenin with either BCL9 or BCL9-2.

Transcriptional Regulation inSaccharomyces cerevisiae: Transcription Factor Regulation and Function, Mechanisms of Initiation, and Roles of Activators and Coactivators

“…Over the past 10 years, a combination of biochemical, genetic, and structural experiments has conclusively identified relevant targets for some mammalian and yeast activators (e.g., Stevens et al 2002;Yang et al 2004;Green 2005;Sampietro et al 2006;Waters et al 2006;Thakur et al 2009;Herbig et al 2010;Jedidi et al 2010). In general, these targets are located in coactivator complexes and chromatin-remodeling or -modifying factors rather than in subunits of the general transcription factors.…”

Structure-Based Design of 1,4-Dibenzoylpiperazines as β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction Inhibitors

“…23,27,28 SiteMap 35 was used to calculate the three-dimensional energy maps around the BCL9 L366/I369/L373 binding site and highlight favorable sites for a specific functional group. The molecular interaction fields (MIFs) for hydrophobic interactions were mainly from the upper pocket that is lined with the side chains of A152, L156, L159, L160, V167, K170, A171, and M174 of β-catenin, as shown in Figure 1A.…”

Prostate Cancer Progression to Androgen Independent Disease: The Role of the Wnt/β-Catenin Pathway

“…Along with -catenin, many other co-activators of TCF have been identified. BCL9 is an adaptor protein proposed to aid transactivation by providing docking sites for other transcriptional machinery such as pygopus (Sampietro et al, 2006). BCL9 has not only been found to interact with -catenin/TCF complex to activate transcription, but also been found to sequester -catenin in the nucleus (Kireghoff et al, 2006).…”

“…The crystal structure of acatenin/BCL9/Tcf-4 complex revealed that BCL9 interacted with -catenin at a region Nterminal to the structural groove of the armadillo repeat domain. The -catenin binding domain on BCL9 forms an -helix, but unlike other co-activators, the helix does not overlap the binding sites of other -catenin partners and can be mutated to prevent propercatenin-BCL9 binding without compromising the integrity of other indispensible interactions (Sampietro et al, 2006). Sampietro et al, (2006) demonstrated that simultaneous mutations within hydrophobic pockets of the first armadillo repeat, especially on residues L156A and L159A, effectively abolished BCL9 binding but not that of E-cadherin andcatenin, the only two known proteins that bind to the same region on -catenin.…”